Studying Chemotherapy-Induced Neuropathic Pain Models with iPSC Derived Sensory Neurons

Many commonly-used chemotherapy drugs also carry the risk of debilitating neuropathic pain. In severe cases this can even result in the discontinuation of a cancer treatment, but through understanding the mechanisms within chemotherapeutics that induce neuropathic pain, researchers aim to develop specific treatments to alleviate the condition.

These treatments will work in spite of the dose-limitation imposed on chemotherapeutics, and may also offer utility for other serious conditions including multiple sclerosis, diabetes and HIV.

The traditional methods for neuropathic pain research have involved heavy use of immortalized cell lines, primary human neuronal cells, or animal models. However, there have recently been concerns over misidentification or phenotypic drift from the original host and immortalized cells have fallen from favor.

Primary human neuronal cells are known to be difficult to culture, and animal studies are costly in both time and money, with findings infrequently translating properly to humans. These reasons have led researchers to turn to iPSC-derived sensory neuronal cells for neuropathy research. These cells are more relevant to human physiology, are relatively inexpensive in comparison, and can be mass produced in a way to acquire reliable and consistent results.

This article will discuss the use of animal nociceptors in studying neuropathic pain, as well as iPSC-derived sensory neuron progenitors.

Animal Nociceptors for the Study of Neuropathic Pain

Nociceptors are specialized peripheral sensory neurons that are active as part of chronic pain conditions including those related to chemotherapy. A common technique in scientific studies is to use rodent nociceptors to understand mechanisms of pain perception. One example is the 2015 study by Park et al., where mice were treated with Cisplatin and then examined for how neuropathic pain developed and the methods of its alleviation.

It was found that mice treated with Cisplatin exhibited allodynia (a pain response from stimuli that would not usually cause pain) and that this could be countered with the anti-epileptic drug Gabapentin to reduce the pain.

Although rodent model systems have in the past been used to advance our understanding of neuropathic pain etiology and treatment, there are several factors that make translating such models into man more difficult. For instance, while Paclitaxel and Cisplatin are being widespread use in the treatment of female patients, it is male animals that are primarily used for chemotherapy-induced neuropathic pain. Another possible factor is how the drug dose or mode of delivery varies between animal studies.

The effect limitations are further heightened due to critical differences between rodent and human nociceptors at the molecular level. In 2017, Rostock et al. performed a comprehensive comparative analysis of well-known nociceptive markers in human and mouse dorsal root ganglia using fluorescent in situ hybridization.

They found greater co-expression of Trpv1 with TrkA, and of Ret with TrkA, in the human neurons than in the mouse neurons. These results were also observed for Na v 1.8 and Na v 1.9, both of which are involved in pathological pain. Whilst there is still value in using rodent models for neuropathy research, it is important to exercise caution when drawing any experimental conclusions.

iPSC-Derived Sensory Neuron Progenitors

AXOL scientists have used small molecule inhibitors to differentiate iPSC into sensory neuron progenitors which are extremely well suited for studying chemotherapy-induced neuropathic pain. Using their thorough characterization process, the cellular expression has been confirmed along with the function of various ion channels that are a key part of nociception. Ion channels studied include the dorsal root ganglion (DRG) specific voltage-gated sodium channels Na v 1.7, Na v 1.8 and Na v 1.9, and the transient receptor potential (TRP) ion channels, TRPV1, TRPA1 and TRPM8.

As part of this research AXOL characterized their iPSC-derived sensory neuron progenitors using a broad set of methods. Sodium channel RNA expression analysis has been measured by cDNA PCR, and  patch clamping was performed in order to assess various ion channels via electrophysiology.

The response to various stimuli was recorded, with temperature used as well as natural substances capsaicin, menthol and allyl isothiocyanate (wasabi). A multi-electrode array system (MEA) was used to evaluate cellular electrical activity, while additional visual confirmation of ion channel expression was provided via immunocytochemistry.

A clear pain response has been shown through the administration of chemotherapy drugs to AXOL’s iPSC-derived sensory neuron progenitors. The application of Vincristine, for example, demonstrated a sharp increase in firing rate, with a slower cellular response to that seen following the application of capsaicin, menthol and allyl isothiocyanate.

Cold hypersensitivity was seen following oxaliplatin treatment, a side effect that has been well-documented for this chemotherapeutic, which is understood to be attributable to the remodeling of ion channel expression in nociceptors.

AXOL also supplies expertly optimized growth media to complement their iPSC-derived sensory neuron progenitors, to aid in their successful culture and propagation, along with unrivaled technical support.

New: Achieve Faster Maturation, Quicker Results and Enhanced Marker Expression.

MATURATION MAXIMIZER is a fully defined media supplement to enhance the existing sensory neuron maintenance medium (ax0060) and  works by mimicking in-vitro, the cell to cell communication and interaction factors which occur when these cells are in their innate environment. The supplement is known to contain factors present in the peripheral nervous system and in particular the peripheral environment of sensory neurons."

About AXOL Biosciences

Axol specializes in human cell culture.

Axol produces high quality human cell products and critical reagents such as media and growth supplements. We have a passion for great science, delivering epic support and innovating future products to help our customers advance faster in their research.

Our expertise includes reprogramming cells to iPSCs and then differentiating to various cell types. We supply differentiated cells derived from healthy donors and patients of specific disease backgrounds. As a service, we also take cells provided by customers (primary or iPSC) and then do the reprogramming (when necessary) and differentiation. Clearly, by offloading the burden of generating cells, your time is freed up to focus on the research. Axol holds the necessary licenses that are required to do iPSC work.

The package wouldn't be complete without optimized media, coating solutions and other reagents. Our in-house R&D team works hard to improve on existing media and reagents as well as innovate new products for human cell culture. We also supply a growing range of human primary cells; making Axol your first port of call for your human cell culture needs.

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Last updated: Feb 18, 2020 at 11:30 AM


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